Penicillin salt suspensions



Patented Mar. 6, 1951 PENICIILIN SALT SUSPENSIONS Henry C. Miller,Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis,Ind., a corporation oflndiana No Drawing. Application January 8, 1948,Serial No. 1,277

6 Claims. (Cl. 167- 58) I This invention relates to penicillin salts andmore particularly to improvements in oil suspensions of insoluble saltsof penicillin.

It has recently been discovered that certain" organic salts ofpenicillin having a substantial insolubility in water and oil arevaluable in the treatment of infections for which penicillin itself iscommonly used. and that these insoluble organic salts possess anadvantage over aqueous solutions of the water-soluble metal salts ofpenicillin in that the duration of action of the penicillin is greatlyenhanced. Thus, for example, only one or two parenteral administrationsof the insoluble organic penicillin salts are required per diem in placeof the six or more injections required when solutions of water-solublepenicillin salts are being administered.

The water-insoluble organic salts of penicillin which are capable ofthis unexpected prolongation are administered as suspensions in aqueousor oleaginous vehicles. When aqueous suspensions are used, thesuspension must be freshly prepared because of the well knowninstability of penicillin in the presence of moisture. However, in thecase of oil suspensions, the subject with which my invention isconcerned, no substantial amount of moisture is present in thepreparation and in such mixtures the penicillin salts are stable over along period of time. According y. it is most convenient to supply oilsuspensions to the trade, and to furnish the preparations in bottlescontaining the insoluble penicillin salt in finely divided form alreadymixed with the oil vehicle. The insoluble salt of penicillin, which ofcourse is finely divided to permit its free passage through the lumen ofthe hypodermic needle, does not remain in suspension, however, andbefore parenteral administration it is necessary for the technician orphysician to resuspend the salt by agitating the preparation, as byshaking. It has been found that after standing for a period of a fewdays the finely divided salt which separates from the oil vehicle formsa stable mass of solid material which is resuspendable only by prolongedand violent agitation of the bottle containing the penicillin-oilmixture. The reason for the formation of this stable layer of solidmaterial is not understood.

but whatever its cause, it makes diflicult the reform suspensions of thesalts. Other objects will become apparent from the followingdescription.

In the accomplishment of the above and other objects I have discoveredthat readily resuspendable mixtures of finely divided insoluble organicsalts of penicillin in oleaginous vehicles are obtained when there isadded to the oleaginous mixture a small amount of one or more agentscommonly classified as emulsifying agents. The small amount ofemulsifying agent which is added is not sufllcient to produce a stablesuspension or even to cause any observable inhibition of the separationof the penicillin salt from the oil vehicle, but surprisingly, for somereason unknown to me, the small amount of agent does prevent theseparated salt from forming the solid mass of salt which resistsresuspension. Mixtures of insoluble organic penicillin salts andoleaginous vehicles prepared in accordance with this invention, unlikethose which have hitherto been used, may be mixed by mere gentleshaking, to produce uniform and complete suspensions of the insolublepenicillin salts in the vehicles, even after the mixtures have stood forlong periods of time.

In the provision of novel compositions according to my invention, caremust be exercised in the selection of the emulsifying agents used toprevent the formation of the undesirable stable layer of insolublepenicillin salt, and especially so since the compositions are to beadministered parenterally as medicaments. The agents chosen must benontoxic, must be oil-soluble, must be substantially free fromirritating properties, must not impart undesirable odor or color to themedicament and must have no untoward action upon the oil vehicle or theinsoluble penicillin salt. I have found that emulsifying agents fullymeeting the above medical and other requirements are compositionscomprising a group consisting of the fatty acid partial esters ofhexitol anhydrides, including such anhydrides as sorbitans, sorbides,mannitans and mannides, and the polyalkylene derivatives of the aboveanhydrides. Preferred compounds of the above described types of agentsare those which contain fatty acid residues having from about 12 toabout 18 carbon atoms, for example the residues of oleic, lauric andstearic acids. The preferred polyalkylene derivatives mentioned aboveare those prepared by reacting ethylene oxide or propylene oxide withthe partial fatty acid esters of hexitol anhydrides, with the amount ofethylene oxide or propylene oxide introduced in the molecule notexceeding a ratio of about 25 molecules of oxide to one of theanhydride.

The amounts of the above emulsifying agents employed in compositionsprepared in accordance with my invention are much less than the range of2 to 5 percent commonly employed in preparing oil-water emulsions. In myinvention, although concentrations of 2 or more percent by volume areeffective, efiicient results are obtained when the concentration ofemulsifying agent employed in the penicillin salt-oil mixture does notexceed one percent, and surprisingly the effectiveness of theemulsifying agent in producing an easily redispersible penicillin saltmixture attains its optimal value when the concentration is about 0.125percent. It is difficult to account for this surprising optimalconcentration and I I know of no suitable explanation of thisphenomenon. I have found that a mixture of emulsifying agents of theabove types may be employed and that the most effective results areobtained when the total concentration of the mixure of emulsifyingagents is about 0.125 percent. Thus, preferred compositions prepared inaccordance with my invention contain emulsifying agents in effectiveamounts up to about 1 percent, and most desirably they contain aconcentration of about 0.125 percent by volume.

Illustrations of novel compositions and their preparation in accordancewith my invention are set forth in the following specific examples.

Example .1

24 liters of sesame oil, 24 cc. of the polyethylene oxide derivative ofsorbitan mono-oleate and 13.5 cc. of sorbitan mono-oleate are mixed withstirring and the mixture is sterilized by heating it to about 150 C. for3 hours. The mixture is cooled to about 45 C., and under sterileconditions and with vigorous stirring 9 kg. (9 billion units) of theprocaine salt of penicillin in finely divided condition (200 meshscreen) are added. The above composition has a total volume of about 30liters and on a percentage basis contains about 0.125 percent ofemulsifying agent. The sterile suspension thus obtained is then placedin small sterile bottles suitable for distribution to the trade, andsealed. During the filling of the bottles with the sterile suspension ofprocaine penicillin in oil, it is of course necessary to maintain aneven distribution of the penicillin salt in the oil by agitation of themixture.

A sample of the oil suspension of procaine penicillin prepared inaccordance with the above procedure was allowed to stand for two weeks.At the end of the two weeks period the mixture was found to be readilyresuspendable by gentle shaking for a few seconds. In comparison, asample of procaine penicillin suspended in sesame oil without theaddition of the emulsifying agent, and which was allowed to stand fortwo weeks, was found to be resuspendable only upon violent shaking ofthe sample for a period of about minutes.

A sample of procaine penicillin oil suspension prepared in accordancewith the above procedure and a sample of procaine penicillin in sesameoil which contained no emulsifying agent were centrifuged at 2500 R. P.M. for about 40 minutes to cause complete separation of the suspendedprocaine penicillin salt. The procaine penicillin salt in the mixture ofoil and emulsifying agent was readily resuspendable upon gentle shakingfor a few seconds, whereas the procaine penicillin salt in the plain oilvehicle was resuspendable only upon violent and prolonged'shaklng formanyminutes.

Example 2 The procedure of Example 1 may be followed in preparing acomposition comprising the following ingredients and proportionsthereof:

Cottonseed oil ml 1200 Procaine penicillin g 450 sorbitan mono-oleate ml3.7

The above composition has a total volume of about 1500 ml. and containsabout 0.25 percent of emulsifying agent.

Example 3 The following composition containing about 1 percent ofemulsifying agent may be prepared according to the procedure of Example1:

Peanut oil ml 1000 Profiavin penicillin g 250 Polyoxyalkylene derivativeof sorbitan monopalmitate ml 9.2.5

Example 4 The following composition containing about 0.08 percent ofemulsifying agent may be prepared according to the procedure of Example1:

Sesame oil ml 2400 Procaine penicillin g 500 Gentian violet salt ofpenicillin g 400 Sorbitan mono-oleate ml 2.4

dients may be employed.

As is known to the art, a wide variety of oleaginous media may beemployed in the preparation of penicillin salt suspensions suitable fortherapeutic purposes. Suitable oleaginous dispersion media comprisingoils and liquid oil-wax mixtures which may be referred to asphysiologically compatible oils, and with which my invention isoperative, include both parenterally and topically useful oils. Oilssuitable for parenteral administration include the non-drying vegetableoils, such as rapeseed, cottonseed, poppy seed oil and the like, as wellas the lower aliphatic esters of the fatty acids, for example ethyloleate and ethyl stearate. An illustrative example of an oil suitablefor topical application is liquid petrolatum. Examples ofphysiologicallycompatible waxes are beeswax and spermaceti.

As is known, for therapeutic purposes, compositions containing theinsoluble penicillin salt in finely divided form are desirable. Thisfine division is especially desirable in compositions intended forinjection purposes to avoid the tendency of the particles of thepenicillin salt mechanically to pack" in the lumen of the hypodermicneedle. Thus it is the practice to provide penicillin salt-oilsuspensions in which the penicillin has been ground or powdered until itwill pass through a ZOO-mesh screen. However, the size of the penicillinsalt particles is not critical for the purposes of my invention, and myinvention is operative with penicillin salt particles even of such sizeas will pass through a 40-mesh or coarser screen. In general, it may besaid that the more finely divided the penicillin salt, the moretenaciously the particles of salt adhere to each other and the moredifiicultly the solid mass which settles out is redispersible. Hence, myinvention is of greater importance in connection with penicillinsalt-oil suspensions in which the penicillin salt is in a finely dividedstate, a condition which is presently preferred for therapeuticcompositions.

I claim:

1. A readily redispersible substantially waterfree therapeuticcomposition comprising a major proportion of an oleaginous vehicle, aminor proportion of a finely divided water-insoluble, and

oil-insoluble organic penicillin salt and an amount eifective to causeredispersion and less than about one percent by volume of at least oneemulsifying agent of the group consisting of the fatty acid partialesters of hexitol anhydrides and their polyalkylene oxide derivativesI2. An injectable readily redispersible therapeutic composition beingsubstantially water-free, comprising a non-drying vegetable oil, afinely divided water-insoluble, and oil-insoluble organic penicillinsaltand in total amount about 0.125 percent by volume of at least onemember of the group consisting of the fatty acid partial esters ofhexitol anhydrides and their polyakylene oxide derivatives.

3. A readily redispersible substantially waterfree therapeuticcomposition comprising a nondrying vegetable oil, finely dividedprocaine penicillin and an amount effective to cause redispersion andless than about one percent by volume of at least one member of thegroup consisting of the fatty acid partial esters of hexitol anhydrides"and their polyalkylene oxide derivatives.

4. A readily redispersible substantially waterfree therapeuticcomposition comprising sesame oil, finely divided procaine penicillinand an amount effective to cause redispersion and less than about onepercent by volume of at least one member of thegroup consisting of thefatty acid partial esters of hexitol anhydrides and their polyalkyleneoxide derivatives.

5. A readily redispersiblesubstantially waterfree therapeuticcomposition comprising sesame oil, finely divided procaine penicillinand an amount effective to cause 'redispersion and less than about onepercent by volume of a mixture of sorbitan mono-'oleate and thepolyethylene oxide derivative of sorbitan mono-oleate.

6. A composition according to claim 5 in which the mixture of sorbitanmono-oleate and the poly-' ethylene oxide derivative of sorbitanmono-oleate is present in a concentration of about one eighth of onepercent by volume.

HENRYC. MILLER.

REFERENCES CITED The following references are of record in the file ofthis patent:

OTHER REFERENCES

1. A READILY REDISPERSIBLE SUBSTANTIALLY WATERFREE THERAPEUTICCOMPOSITION COMPRISING A MAJOR PROPORTION OF AN OLEAGINOUS VEHICLE, AMINOR PROPORTION OF A FINELY DIVIDED WATER-INSOLUBLE, AND OIL-INSOLUBLEORGANIC PENICILIN SALT AND AN AMOUNT EFFECTIVE TO CAUSE REDISPERSION ANDLESS THAN ABOUT ONE PERCENT BY VOLUME OF AT LEAST ONE EMULSIFYING AGENTOF THE GROUP CONSISTING OF THE FATTY ACID PARTIAL ESTERS OF HEXITILANHYDRIDES AND THEIR POLYALKYLENE OXIDE DERIVATIVES.